Most cancer deaths are caused by metastasis to distant organs, and treatment is usually ineffective if withheld until metastasis is clinically detectable. Fortunately, recent work in several cancers has shown that molecular information obtained from the primary tumor can predict metastatic risk, thereby permitting prophylactic treatment of high-risk patients at an early stage of metastasis. Ocular melanoma provides an ideal model for developing and validating such a preemptive strategy. Up to 50% of ocular melanoma patients die of metastasis despite successful treatment of the primary eye tumor, indicating that most patients who die of metastasis have microscopic, undetectable metastatic disease prior to ocular treatment. Metastatic disease usually goes undetected for 2-5 years after diagnosis and treatment of the primary ocular tumor, which allows the metastatic tumor cells to undergo up to 30 doublings, resulting in a large tumor burden of genetically deregulated cells that are highly resistant to treatment. Consequently, by the time metastatic disease is detected, death inexorably occurs within 5-7 months. Ocular melanoma cells are likely to be sensitive to many new molecular therapies, if treatment could be instituted earlier in the metastatic process. These observations suggest that early identification of high-risk patients and prophylactic treatment for presumptive metastatic disease may improve survival. Unfortunately, there are currently no biomarkers for ocular melanoma that are sufficiently accurate and/or practical to identify high-risk patients. To address this deficiency, we developed a gene expression profile that identifies high-risk patients with far greater accuracy than previous prognostic indicators. Conversion of this RNA-based assay to an immunohistochemical (IHC) platform is critical for continued development of this discovery. An IHC platform would be practical for routine clinical use, and it would allow the assay to be validated using archival tumors. Here, we propose experiments to identify and validate lead IHC markers in two independent tumor sets, then to evaluate the predictive accuracy of the IHC-based assay in a large patient cohort from the Collaborative Ocular Melanoma Study. These studies are likely to impact patient care by identifying high-risk patients, providing a framework for testing prophylactic therapies, revealing new therapeutic targets and offering new mechanistic insights into cancer progression.